Lecture 23: Pathogenesis of Colorectal Cancer and Strategies for Prevention Flashcards
What is the basis for understanding the development and management of CRC?
Adenoma-Carcinoma Sequence
Normal colonic mucosa adenoma carcinoma
What stem cell populations are in the colon/small intestine crypts?
2 different stem cell populations
- +4 markers
- CBC (columnar basal cell) markers
- leads to absorptive enterocytes, goblet cells, paneth cells, entero-endocrine cells, and tuft cells
What is the significance of stem cell populations at the colon/small intestine?
There is an exquisite proliferation and differentiation gradient at the crypt
2 stem cell populations that adapts to injury at these sites
If this adaptational situation goes awry, you get polyps and cancer
What is an ACF (aberrant crypt focus)?
A hyperproliferative crypt
What is a polyp?
An excessive growth that occurs over time (years)
Hyperproliferative state that leads to excessive state
What is the definition of adenomatous polyp?
Low grade dysplasia
Can be sessile or pedunculated
What triggers the hyperproliferative state?
Mutation or loss of APC in the wnt pathway
Chromosome 5p
How do you progress from early to intermediate adenoma?
Mutation of the KRAS gene
How do you progress from intermediate adenoma to late adenoma to carcinoma?
Loss of DCC
Then loss of p53
What does APC stand for? Significance?
Adenomatous polyposis coli
A tumor suppressor gene
Discovered as gene mutated in FAP (familial adenomatous polyp)
First gene inactivated in 80% of sporadic colon adenomas and carcinomas
What is the normal function of APC?
APC protein sequesters beta-catenin by recruiting other proteins
APC DEGRADES B-catenin
Fucks up B-catenin function
What happens if Wnt ligand binds to Wnt receptor?
It disengages B-catenin from APC complex
B-catenin then leads to upregulation of c-myc and cyclin D1
So B-catenin = GROWTH
What happens when you have aberrant APC?
Proliferation increased and upregulated
Apoptosis decreased
How do APC mutations come about?
Two hit hypothesis
1 germline mutation
1 sporadic hit
What is the other 20% of sporadic CRC due to aside form APC mutation?
Microsatellite instability
Associated with abnormal expression of any one of at least four genes (MSH2, MSH6, MLH1 and PMS2)
Loss of mismatch repair genes = microsatellite instability = sporadic CRC
What is microsatellite instability?
When you have two nucleotides instead of one that gets inserted into a mismatch repair
This leads to a daughter chromosome that is one chromosome longer and thus abnormal
What is MMR?
Mismatch repair
What are the key characteristics of microsatellite instability?
- mismatch repair deficiency results in microsatellite instability
- Loss of activity can occur with germline mutations or by an epigenetic mechanism with gene silencing by hypermethylation of promoter region (MLH1)
- TGFBRII and other genes have polyA sequences that are at risk for mutation
- MMR genes don’t cause cancer but allow mutations in regulatory genes leading to cancer
What is the association between COX-2 and CRC?
Increased expression of COX-2 in colon cancers
Generates prostaglandins
Inhibition of cox-2 in animal models and in humans results in inhibition of tumor cell growth
What are the risk factors for colorectal cancer?
- Aging
- Personal history of CRC or adenomas
- High fat, low-fiber diet
- IBD
- Family history of CRC
- Inherited colon cancer syndromes
What are the INHERITED CRC syndromes?
- FAP
a. Gardner’s Syndrome
b. Attenuated FAP (AAPC or AFAP)
c. Turcot’s Syndrome - HNPCC/Lynch Syndrome
a. Muir-Torre Syndrome
b. Turcot’s Syndrome
What are the hallmark features of FAP?
100 of polyps 5-7 cm in length
Average age of onset is 16
Cancer in mid 40s
What is the chance of cancer for untreated polyposis?
Leads to 100% risk of cancer
Risk of extracolonic tumors like upper GI (duodenal), desmoid, osteoma, thyroid, brain, skin (ie Gardner’s Syndrome)
What is Gardner’s Syndrome?
A variant of FAP
Features of FAP:
i. desmoid tumors (tumors that arise from fibroblasts)
ii. Osteomas
iii. Supernumerary teeth
iv. Soft tissue skin tumors
v. Congenital hypertrophy of retinal pigment epithelium
What are the genetics of FAP?
Auosomal dominant
Caused by APC mutation
30% have de novo germline mutations
Two hit hypothesis = one inherited APC allele is mutated
-second hit = sporadic during life
-loss of heterozygosity
De novo germline mutations occur in 30% of FAP cases
Some FAP features correlate with specific APC gene regions!!! (slide 41)
